ARTIFICIAL PLACENTA FOR IN VITRO DRUG SCREENING

用于体外药物筛选的人工胎盘

• 批准号: 2563257
• 负责人: DOUGLAS A KNISS
• 金额: $ 9.87万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2563257
• 关键词: biological models; bioreactors; cell line; drug screening /evaluation; membrane model; model design /development; placenta; placental transfer; pregnancy disorder chemotherapy; trophoblast; zidovudine

DESCRIPTION: (adapted from the applicants abstract) The placental trophoblast is the cellular conduit for all substances transported between the maternal and fetal compartments. Chemotherapeutic agents which are administered to pregnant women are delivered via the uterine circulation to he placenta where they are transferred to the fetus based upon their physicochemical properties (i.e., molecular size, polarity, ionic stats, etc.). Thus, understanding the principles of drug transport kinetics is important for establishing parameters of therapeutic treatment in pregnant women. In addition, the trophoblast readily metabolizes a variety of agents which can influence their transport to the fetal circulation and their therapeutic efficacy and toxicity. Current models used to study placental transport and metabolism rely on static in vitro systems of short-term primary trophoblast cultures or transformed cells lines derived from choriocarcinomas. Animal models have been useful for organ level physiologic studies, but cannot address cellular or molecular questions of drug metabolism by the placental trophoblast. We have designed a fibrous-bed bioreactor in which an immortal human placental trophoblast cell line (ED27) is maintained in long-term culture and monitored for a variety of physiologic (02 and C02 exchange), metabolic (glucose consumption, lactate production, and LDH release), endocrine steroid hormone and hCG secretion), and molecular (changes in gene expression) events can be evaluated in a single preparation. In aim 1 of this proposal, we will establish the validity of the model system in terms of the above biologic parameters. Aim 2 will then employ this reactor system to study the effect of the anti-HIV drug AZT (Zidovudine) on trophoblast functions. This system should be useful for preclinical evaluation of drugs intended for use in treating maternal and/or fetal complications of pregnancy.

描述：（改编自申请人摘要）胎盘 滋养细胞是所有运输的物质的细胞导管 孕产妇和胎儿室。 化学治疗剂 通过子宫循环传递给孕妇的孕妇 他的胎盘，根据他们的 物理化学特性（即分子大小，极性，离子统计，离子统计， ETC。）。因此，了解药物运输动力学的原理是 对于建立孕妇治疗的参数很重要 女性。 此外，滋养细胞很容易代谢各种代理 这会影响他们运输到胎儿循环及其运输 治疗功效和毒性。 用于研究胎盘的当前模型 运输和代谢依赖于短期的静态体外系统 原代滋养细胞培养物或转化的细胞系。 绒毛膜瘤。 动物模型对器官水平有用 生理研究，但不能解决细胞或分子问题 胎盘滋养细胞的药物代谢。 我们设计了一个 纤维床生物反应器中，不朽的人胎盘滋养细胞细胞 线（ED27）保持在长期文化中，并监视了一种多样性 生理学（02和C02交换），代谢（葡萄糖消耗， 乳酸产生和LDH释放），内分泌类固醇激素和HCG 分泌），分子（基因表达的变化）事件可以是 在单个制备中进行评估。 在本提案的目标1中，我们将 根据上述生物学建立模型系统的有效性 参数。 AIM 2然后将采用此反应堆系统来研究效果 抗HIV药物AZT（Zidovudine）在滋养细胞功能上的 这个系统 对于旨在用于使用的药物的临床前评估应该有用 治疗妊娠的母亲和/或胎儿并发症。